Piperazines of formula A wherein R is a lower alkyl, Ar is an unsubstituted or substituted aryl or heteroaryl, and Q is a hydrogen, CO-(lower) alkyl, CO-cycloalkyl, or CO-aryl, are potent 5HT1A receptor binding agents. U.S. Pat. No. 6,127,357 teaches such piperazine derivatives that are useful in the treatment of Central Nervous System (CNS) disorders. Piperazine derivatives of formula A contain an asymmetric carbon so they may exist in two optically active forms. It is now well understood that enantiomers bind to receptors with different potency and selectivity, they may have different metabolic fate and produce different side effects. WO 9703982 teaches that preferred enantiomers of piperazines of formula A display improved 5HT1A binding affinity and bioavalability. Therefore, an efficient, operationally facile, inexpensive and safe alternative process for making these homochiral piperazines is desirable.
WO 9533725 teaches a method for synthesizing some chiral piperazines of formula A by alkylation of the corresponding 1-aryl-piperazine with enantiomerically pure 2-(5-methyl-2,2-dioxido-1,2,3-oxathiazolidin-3-yl)pyridine.
One conventional approach to creating 1,4-disubstituted piperazines is via bis-alkylation of primary amines with bis(2-chloroethyl) amines, the so-called nitrogen mustard gases. A few optically active piperazines, structurally unrelated to formula A, have been prepared by condensation of an N-substituted bis(2-chloro-ethyl)amine with a selected chiral amine according to Natsuka et al. in J.Med.Chem. 1987, 1779 and WO 9424115, and with a natural amino acid according to Acta Pol. Pharm. 1999, 56, p. 41; CA 131: 157745. However, there is a need for a process to make synthetically useful, chiral nitrogen mustard molecules. Chem. & Pharm. Bulletin Japan 1954, 275 describes a conversion of bis(2-chloroethyl)amine into N-bis(2-chloroethyl) aminoacetonitrile, and a related paper in Chem. & Pharm. Bulletin Japan 1957, 487 reports an unsuccessful attempt to resolve the corresponding racemic N-bis(2-chloroethyl)alanine, and tedious resolution of 2-[N-bis(2-chloro-ethyl)amino]propanamide.
Polyfunctional chiral amines are accessible by several multi-step procedures, but a direct displacement of a reactive functional group typically results in racemic amines.
Effenberger et al. (Angew. Chem. 1983, 95[1], 50) reported that triflates react with simple secondary amines under Walden inversion. This process was applied to the syntheses of both (R)- and (S)-α-amino acid esters. The method allows asymmetric formation of C(α),N-bond in a single reaction with a high degree of stereoselectivity, and has been occasionally used with minor modifications (Quadri et al., Biorg. & Med. Chem. Letters 2, 1661, 1992; Taylor et al., Tetrahedron Letters 37, 1297, 1996). Hoffman and Hwa-Ok Kim, Tetrahedron Letters 31, 2953, 1990 replaced triflates with (4-nitrobenzene)sulfonyloxy esters in a reaction with hydrazines.